MIGRAINE PATHOPHYSIOLOGYAND TREATMENTMECHANISMS Despite its very common prevalence, migraine remains an enigmatic disease. The presence of transient neurological signs in a subgroup of migraineurs has long raised a question that still remainscontroversial: are migraine with and without aura two separate entities, or are they different manifestationsof a similar underlying mechanism? The answer to this question will impact not only our understanding of migraine pathophysiology, but also the design of prophylactic treatment strategies. We know from previous research that migraine with aura is most probably a disorder linked with cortical spreading depression (CSD). In this project we will explore whether migraine without aura is also linked with CSD. We will build on our preliminary findings of structural changes in migraineurs with and without aura, and seek answers to the following questions: Is migraine a progressive disease? Is silent CSD happening in migraine without aura? Is silent CSD happening in the cerebellum? Are there specific structural changes related to migraine? The first aim proposes to test the hypothesis that similar pathophysiological mechanisms underlie both types of migraine. Building on our preliminary findings showing specific areas of cortical thickening in migraineurs, we will explore their location andcorrelations with clinical characteristics. Aim 2 will explore whether brain changes in migraine are progressive in nature, and whether we can find 'downstream' impact of changes in the cortex in the white matter. We will use diffusion tensor imaging to explore characteristics of white matter in migraineurs, and test whether, as shown in our preliminary data, these changes are organized along functional pathways. Finally, in aim 3 we will use anatomical and dynamic imaging to explore the cerebellum, a structure that appears to be chronically affected in migraine. We will test the hypothesis that CSD may arise silently in the cerebellum, and that consequent clinical and structural changes are present in the cerebellum of migraineurs. By pursuing our investigations, we believe that we will be able to continue to identify important pathophysiological issues with potentially relevant consequences for the development of new therapeutic approaches for the prevention of migraine.